Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have focused our studies on the role of IL-12 and its receptor in susceptibility to organ-specific autoimmunity and on the role of IL-18 and its receptor in the potentiation of Th1 differentiation. The enhancement of IL-12 receptor expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development. Although the major function of IL-18 is to enhance Th1 differentiation, IL-18 can also induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanism that regulates these diammetrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor (R) alpha-chain expression. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18R expression was observed. IL-12 mediated upregulation of IL-18R expression required interferon-gamma (IFN-gamma). In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18R expression. Thus, positive/negative regulation of the IL-18R by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response. We have also defined the role of IFN-gamma in regulation of the IL-18R and IL-12R beta-chain chain expression. In the absence of IL-4, IL-12-dependent up-regulation of these receptors was independent of IFN-gamma. However, in the presence of IL-4, IFN-gamma functioned to limit the negative effects of IL-4 on expression of both of these receptors. Neutralization of IL-4 restored IL-12 driven up regulation of receptor expression in an IFN-gamma independent fashion. Notably, in the absence of IL-12 and IL-4, IFN-gamma was capable of upregulating IL-12R expression and of priming IFN-gamma producing Th1 cells. These results illustrate the pleiotropic effects of IFN-gamma on regulation of the IL-12 and IL-18 receptors and clearly define the role of IFN-gamma in IL-12-dependent and independent Th1 differentiation. Although IL-12 plays a critical role in the priming of Th1 responses, it is still unclear if fully differentiated Th1 effectors require continued stimulation by IL-12. We have shown that the capacity of a fully differentiated autoreactive Th1 line specific for myelin oligodendrocyte glycoprotein (MOG) to proliferate and to produce IFN-gamma is completely independent of IL-12 or CD40/CD40L interactions. The capacity of this line to induce disease in vivo in cell transfer studies was also IL-12 independent. These results have important implications regarding the therapeutic usefulness of IL-12 blockade in organ-specific autoimmune diseases.